Reconstituting Infusion Device

ABSTRACT

A system and method for a patch-like, self-contained multi-component substance infusion device which provides one or more substantially hidden patient needles which can be placed in fluid communication with a fluid reservoir assembly that includes a rigid bladder portion used in conjunction with a non-distensible bladder film, such as a metallized film. The device can be attached to a skin surface via an adhesive contact and a pressurization system provides a pressure to the contents of a fluid reservoir assembly. Improvements to dry powdered formulations for reconstitution for preferred use in the device are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. Non-Provisional patentapplication Ser. No. 11/222,204, filed Sep. 8, 2005 at the U.S. Patentand Trademark Office, which claims priority to U.S. Provisional PatentApplication Ser. No. 60/609,081, filed on Sep. 10, 2004, the disclosuresof both applications being incorporated herein by reference in theirentirety.

This application contains subject matter related to that of U.S.non-provisional patent applications of Shermer et al., entitled“Patch-Like Infusion Device”, Ser. No. 10/623,702, filed on Jul. 22,2003, now U.S. Pat. No. 7,250,037, and Cindrich et al., entitled“Patch-Like Infusion Device”, Ser. Nos. 10/916,649 and 10/916,648, filedon Aug. 12, 2004, the latter now issued as U.S. Pat. No. 7,857,131, theentire contents of all of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates generally to medical devices and methodsfor the preparation and administration of therapeutic or other compoundsto a patient, and more particularly to drug reconstitution andadministration systems and methods which facilitate optimalreconstitution, mixing and dilution of a drug and/or other compound witha liquid diluent, and subsequent administration of the resultant mixturefrom an infusion type device.

BACKGROUND OF THE INVENTION

Infusion therapy is a widely known therapy for patients who requiremedicaments to be delivered over some time period. Diabetic infusionpump therapy, which entails the purchase of an expensive pump that lastsfor about three years, has possibly the largest population of outpatientinfusion therapy. The initial cost of the pump is a high barrier to thistype of therapy. From a user perspective, however, the overwhelmingmajority of patients who have used pumps prefer to remain with pumps forthe rest of their lives. This is because infusion pumps, although morecomplex than syringes and pens, offer the advantages of continuousinfusion of insulin, precision dosing and programmable deliveryschedules. This results in closer glucose control and an improvedfeeling of wellness.

As patients on oral agents eventually move to insulin and their interestin intensive therapy increases, users typically look to insulin pumps.However, in addition to their high cost (roughly 8 to 10 times the dailycost of syringe therapy) and limited lifetime, insulin pumps representrelatively old technology and are cumbersome to use. Also, from alifestyle standpoint, the tubing (known as the “infusion set”) thatlinks the pump with the delivery site on the user's abdomen is veryinconvenient and the pumps are relatively heavy, making carrying thepump a burden.

Therefore interest in better therapy is on the rise, accounting for theobserved growth in pump therapy and increased number of dailyinjections. In this and similar infusion examples, what is needed tofully meet this increased interest is a form of insulin delivery orinfusion that combines the best features of daily injection therapy (lowcost and ease of use) with those of the insulin pump (continuousinfusion and precision dosing) and that also avoids the disadvantages ofeach.

Several attempts have been made to provide ambulatory or “wearable” druginfusion devices that are low in cost and convenient to use. Some ofthese devices are intended to be partially or entirely disposable. Intheory, devices of this type can provide many of the advantages of aninfusion pump without the attendant cost and inconvenience.Unfortunately, however, many of these devices suffer from disadvantagesincluding user discomfort (due to the gauge and/or length of injectionneedle used), compatibility and interaction between the substance beingdelivered and the materials used in the construction of the infusiondevice, and possible malfunctioning if not properly activated by theuser (e.g., “wet” injections resulting from premature activation of thedevice). Long-term drug stability has also been an issue for these typesof devices, and therefore a majority of drugs, when in liquid form mustbe refrigerated.

In order to combat the drug stability problem, storage-stability can beimparted to medicaments by placing them in a dry powder form. Techniquesfor doing this include freeze-drying, spray freeze-drying,lyophilization and the like. However, reconstitution of such medicamentshas been difficult and involves many steps. Additionally, reconstitutedliquids typically do not have the same properties as a liquid drugformulation, at least because bubbles may be formed duringreconstitution.

Various methods to disrupt bubbles in reconstituted formulations havebeen attempted in the past. Most of these methods use application ofultrasonic energy. The ultrasonic effect is based on what is known ascavitation, i.e., cavities containing gas formed by sound waves. Thesecavities collide with each other forming larger cavities that then riseto the surface and dissipate. These methods require specialized andbulky equipment and power sources. Yet another drawback of cavitation isthe momentary, yet intense, burst of heat generated as each bubblecollapses. The heat generated can certainly destroy some activecomponents or unstable drugs in the product. It would be desirable tohave a method for removing bubbles from a reconstituted solution, whichdid not have such issues as high-energy input and heat generation. Othermethods to reduce bubble formation that have been attempted areapplication of a high pressure. It is theorized that high pressuresreduces bubble formation because the rate of bubble collapse isproportional to G, the gradient between external tension and bubbleinternal pressure. The higher external tension can shrink bubbles. Witha decrease in diameter of the bubbles, the increased internal gaspressure forces the gas inside the bubble to dissolve, resulting inbubble collapse as the gas is forced into solution. Nevertheless, thisapproach also requires additional equipment safeguards and is notfeasible for many applications due to either safety or cost concerns.Additionally, a bubble will form again after high pressure is removed,such as when the reconstituted product is drawn out of a pressured vial.

To date, however, there remains a need for a system for theadministration of medicaments where the medicament is in a storagestable dry form, which can be readily reconstituted and directlyadministered via an infusion type device. Additionally, thereconstituted drug should have properties, which mimic the pre-mixedliquid formulation. Accordingly, a need exists for an alternative tocurrent infusion devices, such as infusion pumps for insulin thatfurther provides simplicity in manufacture and ease-of-use for bothinsulin and non-insulin applications.

SUMMARY OF THE INVENTION

The present drug reconstitution and administration system is amulti-component arrangement normally enclosed within a housing whichpermits a concentrated drug or other composition to be mixed with aliquid diluent from a pre-filled cartridge assembly, with the systemfurther permitting the infuser reservoir to be filled with the resultantmixture for patient administration. The system permits drugs to beefficiently stored and handled in concentrated form, and furtherfacilitates dilution or reconstitution of the drugs to the desiredconcentration just prior to administration through the use of theintegrated components of the system.

In accordance with the illustrated embodiments, the present systemincludes a container, or cartridge for containing a drug or othermedicament, with the container having a pierceable stopper for closingthe container. The system further includes an infuser assembly includinga reservoir having a filling end, and a patient needle end defining aflow passage therebetween. The reservoir defines an internal chamber influid communication with the flow passage so that liquid can be movedinto and out of the internal chamber via the flow passage. The reservoirmay be constructed in accordance with the reservoir construction of USpatent application of Cindrich et al., Ser. Nos. 10/916,649 and10/916,648, filed on Aug. 12, 2004, the entire content of which isincorporated herein by reference.

The present system further includes a mixing adapter assembly for mixinga liquid in the reservoir assembly with a medicament in the cartridge.The adapter assembly includes a generally cylindrical receiving inlethaving an access needle for fluid connection with the pierceable stopperof the associated cartridge. By this arrangement, the end of thecartridge, and the stopper positioned therein, can be positioned in oneend of the receiving inlet sleeve of the adapter assembly. The receivinginlet has an inside diameter larger than the outside diameter of theassociated cartridge, thus permitting the cartridge assembly to bepositioned generally telescopically within the receiving inlet duringuse of the system.

The access needle of the receiving inlet and the cartridge assemblyconnect to the flow passage of the reservoir assembly and the patientneedle in selective fluid communication with each other. Optionally, avalve is placed in the fluid path between the patient needle and thereservoir. By this arrangement, the present system permitsreconstitution of a concentrated drug by positioning the drug filledcartridge assembly generally within the open end of the receiving inletwith the components slidably engaged to each other. In thisconfiguration, a liquid, such as a diluent, pre-filled in the internalchamber of the reservoir assembly, can be caused to flow through theflow passage of access needle into the cartridge assembly by action of alow-pressure condition in the cartridge assembly. The reconstitution iseffected by the diluent becoming in contact with the drug. The cartridgeassembly is then slid longitudinally further into the receiving inlet,however, the stopper is prevented from further translation due to theinteraction with the access needle hub. Thus the stopper is fixed inrelation to the housing and is now translated with respect to thecartridge assembly such that the stopper forces the now drug/diluentmixture from the internal chamber of the cartridge and through theaccess needle into the reservoir assembly. The liquid from the reservoirassembly is thus mixed with the medicament from the cartridge within thechamber of the cartridge, and forced under pressure back into thereservoir assembly. The desired diluted drug mixture is thus providedwithin the now filled reservoir assembly, with the now-empty chamberfitted within the receiving inlet.

When mixing is complete, the present system facilitates administrationof the mixture by methods and devices according to US patent applicationof Cindrich et al., Ser. Nos. 10/916,649 and 10/916,648, filed on Aug.12, 2004, the entire content of which is incorporated herein byreference. A general description of the action of the infuser is asfollows: The device is self-contained and is attached to the skinsurface of the user by adhesive disposed on a bottom surface. Onceproperly positioned and activated by the user, a pressurizing systemacts on a reservoir surface within the device can be used to empty thecontents of the partially flexible reservoir through one or more patientneedles via a needle manifold. The substance within the reservoir isthen delivered through the skin of the user by the needles, which aredriven into the skin. It will be understood that other embodiments arepossible in which the pressurizing system is replaced with a differenttype of energy device, which may be mechanical, electrical and/orchemical in nature inter alia gas generation pressurizing means,mechanical actuators, or shape memory alloys.

In the preferred form, the reservoir assembly is provided in a closedform to maintain its sterility, such as by the preferred provision of ablister package with pair of peel-away seals or like closing elementspositioned at respective opposite ends of the adapter assembly. Thearrangement is preferably configured for single-use, and to this end, alocking arrangement is provided which prevents removal of the cartridgefrom the adapter assembly after it has been connected with the receivinginlet.

Additionally, it has been found that pressure treatments of themedicament within the cartridge have an unexpected benefit to thequality of the reconstituted drug/diluent solution. For example, lowpressure conditions in the drug reservoir not only serve the purpose offilling the cartridge with the diluent upon fluid connection to thereservoir, the resultant mixture has a lower observable amount ofbubbles. Additionally in certain applications, it may be desirable toreplace the atmospheric gasses normally present with the drug in thecartridge with inert gasses, inter alia argon, helium to further improvethe reconstitution characteristics.

These and other aspects of the invention are substantially achieved byproviding systems and methods for a patch-like, wearable, self-containedreconstituted substance infusion device which provides one or moresubstantially hidden patient needles which can be placed in fluidcommunication with a content reservoir assembly that includes a rigidbladder portion used in conjunction with a non-distensible bladder film,such as a metallized film. A connection is provided for a reconstitutionfluid and/or dry powdered drug. A push type activation assembly isprovided which can then be used to remove a retaining pin and allow aDisk spring assembly to apply an essentially even and constant pressureto the contents of a reservoir assembly. The push type activationassembly then releases and seats one or more spring-loaded patientneedles into the patient's skin and establishes a fluid communicationpath between the patient needles and the pressurized reservoir contents,thereby delivering an infusion of contents into the skin of the user.Upon completion and removal of the infusion device, a number of safetymechanisms can be engaged to cover the needles for disposal.

BRIEF DESCRIPTION OF THE DRAWINGS

The various objects, advantages and novel features of the preferredembodiments of the present invention will be more readily appreciatedfrom the following detailed description when read in conjunction withthe appended drawings, in which:

FIG. 1A is a top perspective view a patch-like injector or infusorsystem using a two component mixing system prior to activation.

FIG. 1B is a bottom perspective view of the patch-like injector of FIG.1A.

FIG. 2A is a first exploded view of the patch-like injector of FIG. 1Ashowing the reservoir assembly and upper housing.

FIG. 2B is a second exploded view of the patch-like injector of FIG. 1Ashowing the button assembly, needle manifold and lower housing.

FIG. 2C is a third exploded view of the patch-like injector of FIG. 1Ashowing the cartridge assembly and access needle.

FIG. 3 is a plan view of the patch-like injector of FIG. 1A, showingaxes A-A, C-C and B-B.

FIG. 3A is a cross-sectional side view along axis A-A of the patch likeinjector of FIG. 3, shown prior to insertion of the cartridge.

FIG. 3B is a cross-sectional side view along axis B-B of the patch likeinjector of FIG. 3, shown prior to insertion of the cartridge.

FIG. 3C is a cross-sectional side view along axis C-C of the patch likeinjector of FIG. 3, shown prior to insertion of the cartridge.

FIG. 3D is a cross-sectional top perspective view along axis B-B of thepatch like injector of FIG. 3, shown prior to insertion of thecartridge.

FIG. 4A is a cross-sectional side view along axis A-A of the patch likeinjector of FIG. 3, shown after insertion of the cartridge.

FIG. 4B is a cross-sectional side view along axis B-B of the patch likeinjector of FIG. 3, shown after insertion of the cartridge.

FIG. 4C is a cross-sectional side view along axis C-C of the patch likeinjector of FIG. 3, shown after insertion of the cartridge.

FIG. 4D is a cross-sectional top perspective view along axis B-B of thepatch like injector of FIG. 3, shown after insertion of the cartridge.

FIG. 5A is a cross-sectional side view along axis A-A of the patch likeinjector of FIG. 3, shown after access to the reservoir.

FIG. 5B is a cross-sectional side view along axis B-B of the patch likeinjector of FIG. 3, shown after access to the reservoir.

FIG. 5C is a cross-sectional side view along axis C-C of the patch likeinjector of FIG. 3, shown after access to the reservoir.

FIG. 5D is a cross-sectional top perspective view along axis B-B of thepatch like injector of FIG. 3, shown after access to the reservoir.

FIG. 6A is a cross-sectional side view along axis A-A of the patch likeinjector of FIG. 3, shown after transfer of the fluid.

FIG. 6B is a cross-sectional side view along axis B-B of the patch likeinjector of FIG. 3, shown after transfer of the fluid.

FIG. 6C is a cross-sectional side view along axis C-C of the patch likeinjector of FIG. 3, shown after transfer of the fluid.

FIG. 6D is a cross-sectional top perspective view along axis B-B of thepatch like injector of FIG. 3, shown after transfer of the fluid.

FIG. 7A is a cross-sectional side view along axis A-A of the patch likeinjector of FIG. 3, shown after pressurization of the reservoir.

FIG. 7B is a cross-sectional side view along axis B-B of the patch likeinjector of FIG. 3, shown after pressurization of the reservoir.

FIG. 7C is a cross-sectional side view along axis C-C of the patch likeinjector of FIG. 3, shown after pressurization of the reservoir.

FIG. 7D is a cross-sectional top perspective view along axis B-B of thepatch like injector of FIG. 3, shown after pressurization of thereservoir.

FIG. 8A is a cross-sectional side view along axis A-A of the patch likeinjector of FIG. 3, shown after deployment of the needle.

FIG. 8B is a cross-sectional side view along axis B-B of the patch likeinjector of FIG. 3, shown after deployment of the needle.

FIG. 8C is a cross-sectional side view along axis C-C of the patch likeinjector of FIG. 3, shown after deployment of the needle.

FIG. 8D is a cross-sectional top perspective view along axis B-B of thepatch like injector of FIG. 3, shown after deployment of the needle.

Throughout the drawings, like reference numerals will be understood torefer to like parts, components or structures.

DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS

The aspects of the present device described below can be used as aconvenient, patch-like device to deliver a pre-measured dose of asubstance, such as a drug or medication, which has been separated intoat least two components (typically a liquid diluent, and a dry powder),to a user through an adhesive attached infusion device. The device isself-contained and is attached to the skin surface of the user byadhesive disposed on a bottom surface. Typically, the two components aremixed by the device and then transferred to the reservoir. Once properlypositioned and activated by the user, a pressurization system on areservoir surface within the device can be used to empty the contents ofthe partially flexible reservoir through one or more patient needles viaa needle manifold. The mixed substance within the reservoir is thendelivered through the skin of the user by the needles, which are driveninto the skin.

It will be understood that other embodiments are possible in which thepressurization system is a variation of a disk spring, or different typeof stored energy device, which may be mechanical, electrical and/orchemical in nature. It will also be understood that the terms mixing andreconstitution are used interchangeably herein when referring to themixture of drug components in the cartridge and the reservoir.Medicament components to be mixed may be gasses, solids, liquids, drypowders, suspensions, or a mixture of any of these. Although many of theexamples herein are of binary systems e.g. dry powder and diluent, itwill be understood that multiple mixing operations may be performed sothat more than two components may be mixed in a sequential fashion. Aswill be appreciated by one skilled in the art, there are numerous waysof carrying out the patch-like injection or infusor system disclosedherein. Although reference will be made to the embodiments depicted inthe drawings and the following descriptions, the embodiments disclosedherein are not meant to be exhaustive of the various alternative designsand embodiments that are encompassed by the disclosed invention. In eachdisclosed embodiment, the device is referred to as an infusor; however,the device may also inject substances at a much faster bolus rate thanis commonly accomplished by infusor devices. For example, the contentscan be delivered in a period as short as several seconds, or as long asseveral days.

As shown in FIGS. 1A through 8D, the embodiment of certain aspects ofpresent invention can be constructed to provide a patch-like, wearable,self-contained substance infusion device that can be used to deliver avariety of multiple-component medications to a patient e.g. dry powderand diluent. The device also provides for a separated drug containercalled a cartridge, which is filled with at least one component of thedrug to be delivered to the patient. The device provides a hiddenpatient needle or needles prior to and during use, and can be secured toa patient via an adhesive surface. The pressurization of the contents ofthe reservoir can be achieved by removing or displacing the springretention disk, as described in greater detail below, to pressurize thedevice contents and the device can then be further activated via areasonable force applied to the top push surface to seat the patientneedles. Alternatively, the patient may push on the side of the deviceto allow a mechanism to seat the needles. In doing so, the devicefacilitates self-injection and reduces or eliminates variations ininjection techniques between users.

In an exemplary embodiment of aspects of the present invention shown inFIGS. 1A through 8D, an infusion device 1000 includes a reservoirsubassembly 100, including an upper housing 110, a reservoir basesurface 120, at least one Disk spring 130, a retaining pin 140, fillplug 150, septum 160 and reservoir film 170. The infusion device 1000further includes a housing subassembly, including a lower housing 210,and patient needle manifold 220 having at least one patient needle 222and a manifold film 224. The housing subassembly further includes aneedle shield 230 and an adjustable needle cap 240. An adhesive layer250 is disposed upon the lower surface of the lower housing 210, and canbe covered by a removable film (not shown), and a pull handle 260. Aclip, such as an “E” clip can be used to secure the retaining pin 140 tothe pull handle 260. Alternatively, pin 140 may be integrally formedinto pull handle 260. The infusion device 1000 further includes a pushbutton subassembly 300, including at least one patient needle manifolddrive spring 310, a push button slide 320, at least one septum needle330, and a fluid communication tube 350. A button face 360 can beprovided to complete the push button subassembly 300. The infusiondevice further includes cartridge assembly 3000, which contains aportion of the medicament to be delivered to the patient. Cartridge 3000is inserted into housing 110. Subsequently, through a series of steps,medicament components in the reservoir 100 are mixed with medicamentcomponents in the cartridge 3000, and are finally deposited into thereservoir 100 for infusion into the patient via microneedles 222. In thedescription below, the term reservoir is often used to describe theassembled and separate reservoir base surface 120, fill plugs 150, 151,septums 160, 161 and reservoir film 170 of the reservoir subassembly100.

FIG. 1A is a top perspective view of a first embodiment of the infusiondevice 1000. In FIG. 1A, the assembled upper and lower housing 110 and210 respectively is shown, between which the push button subassembly 300is contained. The pull handle 260, described in greater detail below, isshown in a pre-energized, pre-activated position and serves to securethe retaining pin 140 within the device and shield the push button 360from any applied forces. As more clearly illustrated in FIG. 1B, whichis a bottom perspective view of the first embodiment, the pull handle260 is further interlocked with the needle cap 240 and the retaining pin140 via clip 270. Also, the pull handle 260 is optionally furtherinterlocked with the push button slide 320.

As shown in FIGS. 2A through 2C, the embodiment of the present invention1000 can be constructed of these subassemblies to provide a patch-like,wearable, self-contained substance infusion device that can be used todeliver a variety of medications to a patient. The device 1000, shown ina pre-reconstitution, pre-energized, pre-activated position in FIG. 1A,provides a hidden patient needle or needles prior to and during use, andcan be secured to a patient via an adhesive surface. The reconstitutionof the finished drug to be delivered can be achieved by the insertion ofcartridge 3000 into housing 110. The pressurization of the contents ofthe reservoir can be achieved by removing the pull handle 260 to“energize” the device and device contents, and the device can then be“activated” via a reasonable force applied to the push-button 360 toseat the patient needles and establish a flow path between the reservoirand needles. In doing so, the device 1000 facilitates self-injection andreduces or eliminates variations in injection techniques between users.

In FIG. 2A, the reservoir subassembly 100 of the infusion device 1000 isshown, and can be comprised of a rigid portion 120 used in conjunctionwith one or more non-distensible but flexible films 170, such asmetallized films. The reservoir subassembly 100 can contain any numberof substances between either a first and second film, where either thefirst or second film is also positioned against the rigid portion, orbetween a first film and the rigid portion. The reservoir is preferablyfilled with a liquid diluent. The rigid portion 120, or reservoir base,can be comprised of and serve as a hard portion of the reservoir againstwhich the flexible film 170 can be pressed as described in greaterdetail below. As noted above, the reservoir of the embodiment shown inFIG. 2A can be constructed to preferably have a hard shell or innersurface, and at least one flexible film attached about the perimeter ofthe hard shell or inner surface. The flexible film 170 can be heatsealed to the rigid portion 120 to create a chamber, or bladder, forstorage of device contents. As at least one wall of the chambercomprises a flexible film 170, and at least one wall of the chambercomprises a rigid surface, one or more Disk springs 130 can be placedadjacent to the flexible film 170 and used to apply a substantiallyconstant pressure to the flexible film 170, and pressurize the reservoirchamber and contents. Although a disk spring is primarily disclosed, anytype of pressurization system may be used with aspects of the invention.Septum 160 is inserted into rigid portion 120 at recess 1600 to seal theaccess path to microneedles 222, and septum 161 is inserted into rigidportion at recess 1610 to seal the access path to cartridge 3000.Additionally, fill plug 150 is inserted into recess 1500 and fill plug151 is inserted into recess 1510 to provide closure of chamber 127 inreservoir 100.

The reservoir of the reservoir subassembly 100 is further preferablyable to be stored for the prescribed shelf life of the reservoircontents in applicable controlled environments without adverse effect tothe contents and is capable of applications in a variety ofenvironmental conditions. Additionally, the barrier provided by thecomponents of the reservoir do not permit the transport of gas, liquidand solid materials into or out of the contents at a rate greater thanthat allowable to meet the desired shelf life. In the embodiment shownin FIG. 2A, the reservoir subassembly materials are capable of beingstored and operated in a temperature range of approximately 0 to 120degrees F., and can have a shelf life of two or more years. Othervariations of materials may be selected which allow for thermal cyclesto room temperature and back to cold storage, as well as othertemperature operating ranges, beyond 0 to 120 degrees F.

Now referring to FIG. 2C, which shows the cartridge assembly 3000. Thecartridge assembly provides cartridge barrel 3100, which is prismatic innature with a cylindrical cross-section, although any shape may be used.Cartridge barrel 3100 has a button end 3175 and an access end 3125, andan internal portion 3150. At the access end 3125 of cartridge body 3100is fitted a slidable, pierceable stopper 3160. Stopper 3160 is slidablyengaged to the internal diameter 3150 of cartridge barrel 3100. Stopper3160 is slidable from access end 3125 to button end 3175. At the buttonend 3175 of cartridge barrel 3100 is plug 3200, which seals button end3175 of cartridge barrel 3100. Cartridge barrel 3100 also has at leastone tang 3300, and as shown in the drawings two tangs 3300A and 3300B.Tangs 3300 are provided for guiding cartridge 3000 into housing 110 andoptionally for locking cartridge 3000 into housing 110 at the end of themixing step. In an alternate embodiment, cartridge barrel 3100 is atest-tube like structure, with a single opening which forms the accessend, thus eliminating the need for plug 3200. Optionally, plug cover3170 covers plug 3200 for a more pleasing aesthetic appearance. Inanother alternate embodiment, cartridge barrel 3100 is an evacuatedblood collection tube-like structure, with a single opening which formsthe access end, and barrier properties which mimic evacuated bloodcollection tubes, thus eliminating the need for plug 3200. Whenassembled, the components of cartridge assembly 3000 form internalchamber 3500 which is contains a portion of the medicament to be mixedand delivered inter alia a dry powder.

The materials of the cartridge subassembly 3000 are further preferablyable to be stored for the prescribed shelf life of the cartridgecontents in applicable controlled environments without adverse effect tothe contents. Additionally, the barrier provided by the components ofthe reservoir do not permit the transport of gas, liquid and solidmaterials into or out of the contents at a rate greater than thatallowable to meet the desired shelf life. In the embodiment shown inFIG. 2C, the cartridge subassembly materials are capable of being storedand operated in a temperature range of approximately 0 to 120 degreesF., and can have a shelf life of two or more years. Preferably thecartridge subassembly is adapted to contain a vacuum for the entireshelf life of the system. Other variations of materials may be selectedwhich allow for thermal cycles to room temperature and back to coldstorage, as well as other temperature operating ranges, beyond 0 to 120degrees F.

FIG. 2C also shows an exploded view of access needle assembly 2000 whichis a hub having double pointed needle assembly. In this embodiment thedouble pointed needle assembly has separated stopper needle 2400 andseptum needle 2330 affixed to hub 2500. In an alternate embodiment,access needle 2000 is formed from a single double pointed needle havinga stopper end 2450 and a septum end 2350. Access needle 2000 iscontained within and slidably engaged to housing 110. Stopper end 2450is adapted to penetrate stopper 3160 and Septum end 2350 is adapted topenetrate septum 161. Access Needle 2000 provides for a selectable fluidconduit from the chamber 127 of reservoir 1000 to chamber 3500 ofcartridge 3000.

The reservoir of the reservoir subassembly 100 is preferably evacuatedprior to filling, as described in greater detail below. In addition, theshape of the reservoir may be configured to adapt to the type ofenergizing mechanism used, e.g., a disk or Belleville spring 130 havingany number of diameters and height dimensions. Additionally, using anevacuated flexible reservoir during filling minimizes any air or bubbleswithin the filled reservoir. The use of a flexible reservoir is alsovery beneficial when the device is subjected to external pressure ortemperature variations, which can lead to increased internal reservoirpressures. In such case, the flexible reservoir expands and contractswith the contents, thereby preventing possible leaks due to expansionand contraction forces exerted on the fill plugs 150, 151 and septum160, 161. This also helps to eliminate dose variation due to temperatureand pressure fluctuations in the environment. Additionally, a flexiblereservoir ensures the ability of a vacuum in the cartridge to enabletemporary filling of cartridge 3000 for reconstitution, and subsequentre-filling of reservoir 100.

Yet another feature of the reservoir subassembly 100 includes theability to permit automated particulate inspection at the time of fill,or by a user at the time of use. One or more reservoir barriers, such asthe rigid portion 120, can be molded of a transparent, clear plasticmaterial, which allows inspection of the substance contained within thereservoir. The transparent, clear plastic material is preferably acyclic olefin copolymer that is characterized by high transparency andclarity, low extractables and biocompatibility with the substancecontained in the reservoir.

The rigid portion 120 of the reservoir subassembly 100 of FIG. 2Afurther comprises at least one fluid path 128 as shown in FIG. 2A, whichaccesses the main chamber 127 of the reservoir. In the embodiment shownin FIG. 2A, the fluid path 128 exits the main chamber 127 of thereservoir, passing under or through the heat seal area provided aboutthe perimeter of the rigid portion 120 for securing the flexible film170, and into a chamber 129 between a fill-head stopper 150 and a septum160, allowing fluid of the reservoir to travel from the reservoir to theseptum 160. In the embodiment shown in FIG. 2A, the fluid path 128 ispreferably constructed to reduce dead volume and incorporates afill-head receiving geometry.

The septum 160 of FIG. 2A, is positioned between the first fluid path128 and a second fluid path comprised of the septum needle 330, septumneedle manifold 322, and tube 350, and can be an elastomeric plug thatwhen penetrated by a septum spike or septum needle 330, creates asterile flow path between the reservoir and the patient needles 222. Theseptum needle 330, which is used to penetrate the septum 160 and createa flow path between the first and second fluid paths, can include aseptum needle boot that maintains the sterility of the septum needleprior to, and after the boot is collapsed and the fluid path is created.

As described in greater detail below, the septum needle 330 can besignificantly larger than the patient needles 222, such as 25-29 gauges,to allow easier handling and preventing flow restriction. As moreclearly shown in FIG. 8D, the septum needle is sized to engage theseptum 160 and remain buried in the septum 160. This engagement betweenthe septum 160 and septum needle 330 creates a sterile environmentthrough which the septum needle 330 travels when piercing the septum160, such that at no time is the septum needle exposed to a non-sterileenvironment.

Returning to FIG. 2B, a bottom, or lower housing 210 is provided thatcan mate with the upper housing 110 and the reservoir subassembly 100described above. The lower housing 210 can be used to trap and containall remaining components, and can provide snap features to receive andattach components and housing members. The lower housing 210 can alsoinclude one or more guiding features for securing, releasing, anddirecting the button slide 320 and patient needle manifold 220 asdescribed in greater detail below. A break line between units, such asbetween the upper and lower housing units, can be positioned towardvertical center of the device, which creates a more stable assemblysince the push button subassembly described below can be top down loadedinto a substantial housing instead of onto a plate. The upper and lowerhousings 110 and 210 respectively, can then be snap fit or bondedultrasonically to one another.

The disclosed device also contains at least one patient needle 222, ormicroneedle, but may contain several, such as the three microneedlesshown in the push button subassembly 300 of FIG. 2B. Each microneedle222 is preferably at least 31 gauge or smaller, such as 34 gauge, and isanchored within a patient needle manifold 220 which can be placed influid communication with the reservoir. Each microneedle is secured toprevent disassembly from the manifold 220 at any force less than 1pound. The microneedles 222, when more than one is included in thedevice, may also be of differing lengths, or gauges, or a combination ofboth differing lengths and gauges, and can contain one or more portsalong a body length, preferably located near the tip of the needle ornear the tip bevel if the needle has one.

In the embodiment described above, the use of multiple 34 gauge needlesto deliver the reservoir contents is practical as the infusion occursover a longer period than typically associated with an immediate syringeinjection requiring a much larger cannula, or needle. In the disclosedembodiments, any needle can be used which targets preferably either theintradermal or subcutaneous space; however, the embodiment shown in FIG.2B includes microneedles of between 1 and 4 mm in exposed length (i.e.,2 mm), and the arrangement of these patient needles can be in a linearor nonlinear array, and can include any number of needles as required bythe specific application. Other ranges of needle lengths may be usessuch as 0.5 to 1 mm. Furthermore, injections made by the device may bein any tissue space, as it is not required that injection be limited totissue spaces discussed in the context of the specification. The mixingand reconstitution aspects of the invention could be useful inparenteral administration in general (e.g., subcutaneous, intravenous,intramuscular and intradermal delivery) or direct administration ofmedicaments to orifices in the body (e.g. intranasal administration).Thus, although the specific embodiments disclosed herein relate to anintradermal infusion apparatus and method, it should be noted that theinvention is not to be limited to only an intradermal infusion device,as devices having aspects of the invention may be useful in devicesperforming parenteral administration in general.

In FIG. 2B, a push button subassembly 300 is shown and integrates aseptum needle 330, septum needle manifold 322, and push button slide 320into one piece; however, fabrication of the push button subassembly 300may be simplified somewhat by providing a snap-on push button face plate360 to allow for two or more simpler molded button parts. The pushbutton slide 320 also provides a mechanism to secure the patient needlemanifold in a retracted position, and release the manifold when thedevice is properly activated. Tubing 350 which is used to establish afluid path as described in greater detail below exits the septum needlemanifold 322 on the same side as a tubing entry to the patient needlemanifold 220 allowing easier assembly and creating a flexible fluid pathbetween the septum needle manifold and the patient needle manifold. Thepatient needle manifold 220 containing the patient needles 222 isassembled into tracks 324 provided by the button slide 320 and creates astable securing and release mechanism, as described in greater detailbelow. Thus, septum needle 330, septum needle manifold 332, tubing 350,needle manifold 220 and needle 222 provide a selective fluid conduitbetween chamber 127 of reservoir 100 and the patient.

A top view of the first embodiment shown in FIG. 3 that illustrates thealignment and travel between the push button slide 320 and the device,which is required for activation. FIG. 3A is a side elevational view ofthe first embodiment and illustrates the low profile of the device andthe centered positioning of the patient needle opening, which is moreclearly illustrated in the bottom view of the first embodiment shown inFIG. 1B. FIGS. 3A through 8D, illustrate a number of cross-sectionalviews (A-A, B-B, and C-C in FIG. 3) of the present embodiment andillustrate the construction, positioning and operation of eachsubassembly in a pre-mixed (FIGS. 3A-3D), mixing (FIGS. 4A-4D), mixing(FIGS. 5A-5D), filled (FIGS. 6A-6D), energized (FIGS. 7A-7D), and postactivated position (FIGS. 8A-8D), each described in greater detail inseparate sections below.

As shown in FIG. 3A-3D, the infuser device is in a pre mixed state. Thecartridge is outside of the housing and the chambers of the both thereservoir and the cartridges are sealed. Cartridge 3000 is aligned forinsertion into housing 110 to begin the mixing of the medicamentconstituents.

As shown in FIGS. 4A to 4D, which is the first portion of the mixingstep. Cartridge 3000 is at least partially inserted into housing 110such that hub 2500 of access needle 2000 is abutting stopper 3160 andstopper end 2450 of access needle has entered chamber 3500 of cartridge3000 such that communication between chamber 3500 and the interior ofaccess needle 2000 is enabled. As hub 2500 is abutting stopper 3160, anyfurther insertion of cartridge 3000 into housing 110 will cause septumend 2350 of access needle 2000 to penetrate septum 161, since accessneedle 2000 is slidably engaged to housing 110.

As shown in FIGS. 5A to 5D, which is the second portion of the mixingstep which shows Cartridge 3000 inserted into housing 110 slightlyfurther than in FIGS. 4A-4D. Consequently, hub 2500 has been pushed bystopper 3160 such that septum end 2350 of access needle 2000 hasbreached septum 161. A fluid path between chamber 3500, access needle2000, and chamber 127 of reservoir 100 is established; thereby fluidcommunication between chamber 3500 and the chamber 127 of reservoir 100is now enabled, allowing mixing of medicament constituents. Preferably,to draw medicament constituents from chamber 127, into chamber 3500,chamber 3500 has a pre-selected lower pressure with respect to chamber127. Alternatively, the pressures in chamber 127 and chamber 3500 may besubstantially equal and a fluid flow is established by manipulation ofcartridge 3000 to draw constituents into chamber 3500. Alternatively,the pressures in chamber 127 and chamber 3500 may be substantially equaland substantially no fluid flow occurs and mixing occurs substantiallyas shown in FIG. 6A-6D.

As shown in FIGS. 6A to 6D, the contents of chamber 3500 have beensubstantially injected into chamber 127 of reservoir 100 by the furtherinsertion of cartridge 3000 into housing 110. The further insertion ofcartridge 3000 into housing 110 has caused translation of stopper 3160within cartridge 3000 to reduce the volume of chamber 3500. As thestopper translates within carriage 3000, the volume of chamber 3500 isreduced until it reaches a pre-determined dead volume. Preferably, thedead volume of chamber 3500 is minimized. As shown, the medicamentmixture is substantially contained within chamber 127 of reservoir 100.At this point the medicament mixture may be viewed by the patientthrough the clear portions of the reservoir for proper mixturecharacteristics. Further aspects of the invention described hereinprovide for optimization of these characteristics.

As shown in FIG. 7A-7C, which demonstrates the pressurized state, inwhich an exemplary pressurization system in the form of a Disk spring130 is included in the device 1000 for applying an essentially even,constant force to the reservoir to force the contents from thereservoir, and is hereinafter sometimes referred to as a “constant forcespring”. The constant force spring 130 is used to store energy that,when released by device activation, pressurizes the reservoir at thetime of use. The spring 130 is held in a flexed state by a pin 140positioned at the center of a plurality of spring fingers. In doing so,the spring is prevented from putting stress on the film 170 of thereservoir subassembly 100 or any remaining device components duringstorage and reconstitution.

The pin 140, or retaining pin, can be any suitable pin, tube or ring,that is sufficiently rigid to resist spring tension and deformation, andsecure the pin to a removal mechanism, such as a pull handle 260described in greater detail below. The pin 140 should not fail undernormal tensile load or, if part of an assembly, should not disassembleat forces that can be induced by shipping and handling, and resulting ininadvertent activation. Pull handle 260 is provided to aid in theremoval of the retaining pin 140 described above. The pull handle 260 ispositioned adjacent to the bottom surface of the device, and includesone or more members, which extend to one side of the device creating amechanical advantage for the removal of the retaining pin 140. In theembodiment shown, the pull handle 260 includes a member 262 that extendsand shields the button head 360 of the push button subassembly 300. Indoing so, the pull handle 260 prevents the application of a force to thepush button 360 until the pull handle is removed. This preventsaccidental activation of the device via the push button prior to properplacement. Optionally, the pull handle 260 includes a member, whichprevents the application of a force to the push button. In otherversions of this embodiment, the pull handle can include a member thatextends between the push button and the device housing to preventmovement of the push button when a force is applied to the push button.

When the retaining pin 140 is pulled free of the Disk spring 130, thefingers of the spring are released and free to bias towards the film,and in doing so, exert a force on the film lid 170 of the reservoirsubassembly 100. The edge of the spring 130 is trapped between thereservoir and the upper housing, and can be configured to preferablycreate a pressure within the reservoir of from about 1 to 50 psi, andmore preferably from about 2 to about 25 psi, and most preferably fromabout 15 to about 20 psi for intradermal delivery of the reservoircontents. For sub-cutaneous injection or infusion, a range of about 2 to5 psi may be sufficient. The Disk spring can be sized between about 1.15to 1.50 inches in diameter, preferably 1.26 inches, to allow for a full750 microliter delivery. A Belleville washer, or disk spring, exhibits aload characteristic, shown as a percentage of flat position loaddeflection, as the spring travels from a flat or flexed state to arelaxed state. One skilled in the art may select a spring size and rateto deliver a range of volumes.

As shown in FIGS. 7A to 7D, a disk spring 130 is provided to apply asubstantially even and constant pressure to the flexible film 170 of thereservoir subassembly 100, compressing the contents of the reservoirbetween the flexible film 170 and the rigid portion 120, and forcing thecontents from the reservoir through one or more flow paths as shown ingreater detail in FIG. 8D, which illustrates a partial cross-sectionalview of the fluid path and reservoir. As noted above, the reservoir ofFIG. 1A can also be made up of two or more flexible, non-distensiblefilms, wherein the contents can be contained between the films where atleast one film is attached to the rigid portion 120 to provide a rigidbase for compressing and pressurizing the contents of the reservoir. Inyet another embodiment of the reservoir subassembly 100, the flow rateis automatically adjusted from an initial high rate to one or morestepped-down lower flow rates. Additional details of an adjusting flowrate are further discussed in U.S. patent application Ser. No.10/396,719, entitled “Multi-Stage Fluid Delivery Device and Method”,filed on Mar. 26, 2003, the entire content of which is incorporatedherein by reference.

As shown in FIG. 8A-8D an activated position is provided, or in-useposition. As the patient needle manifold 220 remains stationary relativeto the slidable movement of the button slide 320, the activated positionis provided as the button slide is slidably engaged and detented in thisposition. In the activated position, the septum 160 is penetrated, andthe manifold are released and forced downward towards the user's skinsurface, driven by the spring 310. In the embodiment shown, the forcerequired to penetrate the septum 160, move the needle within the septumand release the patient needle manifold 220, in moving to this activatedposition is typically between 2 and 4 pounds.

The patient needle and septum needle manifold assemblies 220 and 322respectively, enable access and discharge of fluid contained within thereservoir and delivery of the fluid to the patient needles 222. Eachmanifold housing therefore contains a number of fluid flow paths forrouting reservoir contents received from the septum needle 330, or otherprotuberance, and any associated tubing or conduits 350, and deliveringthe contents to the patient needles 222 and into the skin of the user.The patient needle manifold 220 in which the patient needles 222 areanchored is in fluid communication with the septum needle manifold 322,in which the septum needle 330 is anchored, by way of a flexible tubing350. Alternatively, tubing 350 could be a conduit formed by thefluid-tight assembly of two or more components.

The patient needle manifold 220 is held in a pre-release, or “up” state,under load, provided by one or more springs 310, by the push buttonsubassembly 300 and lower housing 210. In the first version of securingthe patient needle manifold 220 in an up state described above, thepatient needle manifold 220 slidably engages a set of tracks 324disposed on the button slide 320. As the patient needle manifold 220remains stationary within a chute 212 provided by the lower housing 210,the button slide 320 slidably travels until a track opening 325 alignswith the patient needle manifold 220, releasing the patient needlemanifold 220 from the tracks 324 within the chute.

In each version described above, one or more drive springs 310 exert aforce on the top of the patient needle manifold 220 to drive themanifold when activated, or released from the up state, allowing forpatient needle 222 seating when the manifold is released, and creating afluid path between the septum needle, septum needle manifold, flexibletubing, patient needle manifold and the array of patient needles. Thedrive springs 310 serve to “plant” the needles into the skin via thespring-loaded patient needle manifold 220 which can travel at a speedranging between 15 and 26 miles per hour (between 6 and 12 meters persecond)

The slidable motion of the button slide 320 also pushes the septumneedle 330 through the septum 160, creating a flow path between thereservoir and the septum needle. A septum needle containing manifold 322can be attached or constructed as a component of the button slide 320,and moves with the button slide during activation steps until the septumneedle 330 penetrates the septum boot 340, and subsequently the septum160. Depending upon the sequence desired, prior to, concurrent with, orslightly after the septum needle 330 penetrates the septum 160, thepatient needle manifold 220 is released and bottoms out against the skinsurface, seating the patient needles 222 and thereby initiating flow ofenergized fluid from the reservoir, through the septum needle and septumneedle manifold, through the flexible tubing attached to the septumneedle manifold, and to the patient needles of the patient needlemanifold.

One or more septum needles 330 can be provided, separate from thepatient microneedles 222, allowing greater flow within the completefluid path between reservoir and patient needles. In the embodimentdescribed above, the complete fluid path includes in part, two or moreneedles, specifically, at least one septum needle 330, and at least onepatient microneedle 222. This allows the device to incorporate needlesof different constructions depending upon the fluid path characteristicsdesired. For example, the patient microneedles 222 can include one ormore 34 gauge needles, where the septum needle 330 can include one ormore equal or larger needles as required. Additionally, the separationof the patient and septum needles allows further freedom of movement ofthe patient needles during operation of the device. Furthermore, one ormore reservoirs may be employed in the device, allowing greater oraltered flow characteristics within the complete fluid path betweenreservoir and patient needles.

A flexible tube 350 can be used to connect the septum needle 330 and/orseptum needle manifold 322 to the patient needle manifold 220. Theflexible nature of the tube coupling allows the patient needle manifold220 to move with greater independence from the remaining components ofthe device, allowing more effective needle seating. As such, the term“tubing” 350 encompasses any conduit which may be formed by thefluid-tight assembly of two or more components and allows flow betweenthe desired manifolds. Once properly seated, the patient needle manifold220 completes the fluid path between the flexible tubing 350 and thearray of patient microneedles 222, and the user's skin. As noted above,the patient needle manifold 220 is guided into position by features inthe lower housing 210, and the drive springs 310 described above exert aforce on top of the patient needle manifold 220 allowing for needleseating when the manifold is released. A variety of drive spring optionsexist, including the use of as few as one or as many as four coilsprings, or one or more leaf springs.

The subassembly embodiments presented above are not restrictive, and canbe reconfigured as required in a given application. The embodiment ofaspects of the present invention described above is a push-button designwherein the device is first energized, then positioned and affixed to askin surface, and activated by gently pressing a slide button as shownin FIGS. 7A through 8D. Specifically, the user first removes the devicefrom a sterile packaging and energizes the system prior to adhering thedevice to the skin by removing the pull handle 260 from the bottomsurface of the device as shown in FIG. 7A-&C, in a motion similar toopening a soda can or peeling open an orange. The pull handle 260 ispositioned and extends to one side of the device thereby creating amechanical advantage for the removal of the pull handle and attachedretaining pin 140, which can be removed with no more than a reasonableamount of force that can be exerted by a wide range of users (i.e.typically less than 3 pounds). As shown in FIG. 7A, the removal of thepull handle 260 removes the retaining pin 140, and can alsosimultaneously remove an adhesive cover (not shown) and/or a needle cap240, as described in greater detail below. In yet another version ofthis embodiment, the pull handle 260 can be incorporated with theproduct packaging, such that when the package is opened and the deviceis removed, the retaining pin 140, adhesive cover and/or the needle cap240 is also removed.

Upon removal of the device from the package and prior to use, thefeatures described above allows the user to then inspect both the deviceand the contents therein, including inspection for missing or damagedcomponents, expiration dates(s), hazy or color-shifted drugs, and soforth. After use, the user can once again inspect the device to ensurethe entire dose was delivered. In this regard, the device can include anadministered dose indicator for example, a readable gauge area that isat least 20% of the surface area of the device housing and accurate towithin +/−10% of the labeled dose. Both cartridge 3000 and reservoir 100may be inspected in this manner.

After inspection, cartridge 3000 is inserted into housing 110 whichallows the low pressure of chamber 3500 in cartridge 3000 to draw themedicament from chamber 127 of reservoir 100 into cartridge 3000. Uponmixture of medicament constituents in cartridge 3000 with medicamentconstituents formally in reservoir 100, cartridge 3000 is insertedfurther into housing 110, which moves stopper 3160 within cartridge 3000and expels the mixture from cartage 3000 back into reservoir 100. As themixture is ready for injection it may be further inspected viaobservation through clear portions of reservoir 100. Once the inspectionis complete the user may pull retaining pin 140, thereby pressurizingreservoir 100. Once pin 140 has been pulled a sufficient distance fromthe device to disengage from the spring, the fingers of the Disk spring130 are released and are free to drop against the reservoir film 170within the device. The activation button 360 and button slide 320 of thebutton subassembly 300 can be either interlocked with, and/or shieldedby the pull handle 260, such that the activation button 360 cannot bepushed until the pull handle 260 has been removed, thus preventinginadvertent activation or incorrect order of operation by the user. Onceremoval of the pull handle 260, retaining pin 140, adhesive cover andneedle cap 240 is accomplished as shown in FIG. 7A, the device isenergized and ready for positioning and activation. This energizing stepreleases the Disk spring 130 allowing it to press against the flexiblefilm 170 of the reservoir subassembly 100, pressurizing the reservoirand the substance communication path up to the septum 160, and preparesthe device for activation.

After pressurization, the device is positioned and applied to the user'sskin surface. Like a patch, the user firmly presses the device onto theskin and the lower housing 210 includes a bottom surface that allows forthe adhesive layer 250 to secure the device to the skin of the user.This bottom surface of the lower housing 210 can be flat, contoured, orshaped in any suitable fashion, and includes an adhesive layer 250thereon, which would most likely be covered prior to shipping. Prior touse, the user peels back the adhesive covering, such as a film coveringthe adhesive, thereby exposing the adhesive for placement against theskin. The adhesive should preferably adhere to the bottom surface of thedevice with a peel force of not less than 2 pounds, and include acovering that should preferably release from the adhesive with a peelforce of less than ½ pound. Once removed, the user is then able to placethe device against the skin and press to ensure proper adhesion (i.e.application of a vertical load of 3 pounds). In versions of theembodiment in which a removable needle cover 240 is provided, the needlecover should preferably remove from the device with a force not toexceed 2 pounds.

Once properly positioned, the device is activated by sliding the button360 and attached button slide 320 of the push button subassembly 300towards the center of the device as shown in FIG. 8A. With no more thana reasonable amount of force applied by the user (i.e. between 2 and 4pounds), the activation button can be depressed completely to allowactivation. The button and button slide extends within the device andincludes at least one slot which, in a non-release position, holds thepatient needle manifold 220 up against the compressive force of one ormore driving springs 310.

As the user pushes the button, the first event to occur is the buttonpushing the septum needle 330 through the septum 160, creating a flowpath between the reservoir and the patient needles. As noted above, the“shipping” position has already brought the septum needle and septuminto contact. Further motion of the button then releases the patientneedle manifold 220 as described above, allowing the patient needles 222to seat into the skin of the patient driven by the force of one or moredriving springs 310. At this point, the button 360 and button slide 320locks into place giving a positive audible and tactile feedback to theuser indicating that infusion has begun.

The button subassembly 300 sequence of operation described above can bevaried in other embodiments of the same or similar device. In one suchembodiment for example, as the button is pushed by the user, the firstevent to occur is the patient needle manifold 220 releasing and allowingthe patient needles 222 to seat into the skin of the patient driven bythe force of the driving springs 310. Further motion of the button thenpushes the septum needle 330 through the septum needle boot 340 andseptum 160 to create a fluid path. Either method can be implemented, butfailure modes of each can be different. For example, in an operationsequence in which flow is initiated before the patient needle manifoldis released, if the patient needles fail to seat properly a wetinjection will typically occur.

The flexible tubing 350 in each embodiment connects the septum needle330 or septum needle manifold 322 now in fluid communication with thereservoir, to the patient needle manifold 220 now in fluid communicationwith the user, and is sufficiently flexible to allow the patient needlemanifold to move independently of any other device component. Inaddition, as with the tortuous path established by the patient needlemanifold channels described above, the tubing 350 can also serve as aflow restriction where required.

Once activated, the user typically leaves the device in position, or“wears” the device, for some period of time, such as five minutes toseventy-two hours for complete delivery of the device contents, and thenremoves and discards the device with no damage to the underlying tissue.However, upon intentional or accidental removal, one or more safetyfeatures can deploy as described in greater detail below to shield theexposed needles resulting from activation. The safety features howevercan be configured to not deploy if the button and button slide has notbeen pushed and the patient needles extended.

In addition to the performance advantages described above, anotheradvantage of the embodiment of FIG. 1 described above is the ability tomake two or more distinct, self-contained subassemblies that allow forassembly flexibility. Each subassembly is self-contained and stable, andprovides the ability to separate the reservoir assembly from remainingcomponents, allowing separate filling and inspection of the reservoir,while preventing the unnecessary handling of the remaining components.Additionally, should any of the additional components be discarded, thecostly reservoir contents can be retained in used in another assembly.Also, the reservoir contains no unnecessary parts and as a result,brings a low particle load into filling operations. Also, all storedenergy components are in the body subassembly so they cannot beinadvertently deployed during filling of the reservoir. Specifically, nosprings are included in the reservoir, which prevents the chance ofunwanted spring release during filling. As noted, minimal extraneouscomponents in the reservoir reduce particle load, and only containsnecessary components, such as the reservoir, lid, septum and stopper. Nodangling parts are present, and remaining parts for remainingsubassemblies typically require only drop-in assembly steps.

A further advantage of the embodiment of FIG. 1 described above includesthe location of patient needles near the center of the device footprint.Such placement reduces the effects of needle displacement due to devicemovement, such as “rocking”. The patient needle manifold is constructedhaving a low mass, due in part to providing a separate manifold for theseptum, thus providing a higher patient needle manifold velocity duringactivation. The patient needle manifold is provided with independentdirect drive of patient needles, as the drive springs are locateddirectly over the patient manifold, and serve to drive the patientneedle manifold exclusively. The septum penetration force and bootcollapse force have no influence on patient needle manifold movement.Additionally, there is room to include larger needle spacing and a loweractivation force is sufficient, however, inadvertent activation due tosuch lower forces is prevented by numerous activation lockouts.

Sufficient room is also provided for a traditional septum, as well assufficient room allowing the use of flexible tubing, or any number offlow restrictors, such as capillary tubes, for flow restriction. Thiscan be provided while still maintaining a smaller device footprint.Additionally, the reservoir can be located on top of the device, whichcan allow full and un-obscured view of the drug reservoir through atransparent component, allowing view of the reservoir contents to theuser or manufacturer.

In each embodiment described above, the reservoir subassembly of theinfusion device can be comprised of a rigid portion used in conjunctionwith one or more non-distensible but flexible films, such as metallizedfilms, and can contain any number of substances between either a firstand second film, where either the first or second film is alsopositioned against the rigid portion, or between a first film and therigid portion. The rigid portion, or reservoir base, can be comprised ofand serve as a hard portion of the reservoir against which the flexiblefilm can be pressed as described in greater detail below. The rigidportion can contain a dished out central section and a flange, providedabout the perimeter of the rigid portion to allow for heat-sealing theflexible film, or film lid to the rigid portion and forming a contentreservoir, or chamber, therebetween. As at least one wall of the chambercomprises a flexible film and at least one wall of the chamber comprisesa rigid surface, one or more pressurization systems can be placedadjacent to the flexible film and used to apply a substantially constantpressure to the flexible film, and pressurize the reservoir chamber andcontents. As noted above, the reservoir can also be made up of two ormore flexible, non-distensible films, wherein the contents can becontained between the films and at least one film is attached to therigid portion to provide a rigid base for compressing and pressurizingthe contents of the reservoir. In yet another embodiment of thereservoir subassembly, the flow rate is automatically adjusted from aninitial high rate to one or more stepped-down lower flow rates.Additional details of an adjusting flow rate are further discussed in aU.S. patent application of Jim Fentress et al., Ser. No. 10/396,719,filed Mar. 26, 2003, entitled “Multi-Stage Fluid Delivery Device AndMethod”, the entire content of which is incorporated herein byreference.

The flexible film of the reservoir subassembly can be made ofnon-distensible materials or laminates, such as metal-coated films orother similar substances. For example, one possible flexible laminatefilm which can be used in the reservoir subassembly of the firstembodiment can be comprised of a first polyethylene layer, a secondchemical layer as known to those skilled in the art to provide anattachment mechanism for a third metal layer which is chosen based uponbarrier characteristics, and followed by a fourth layer comprised ofeither polyester or nylon. By utilizing a metal-coated or metallizedfilm in conjunction with a rigid portion, the barrier properties of thereservoir are improved, thereby increasing or improving the shelf lifeof the contents contained within. For example, where reservoir contentincludes insulin, the primary materials of contact in the reservoirsubassembly of the embodiment described above include linear,low-density polyethylene (LLDPE), low-density polyethylene (LDPE),cyclic olefin copolymer (COC) and Teflon. As described in greater detailbelow, the primary materials of contact in the remaining flow path ofthe reservoir contents include polyethylene (PE), medical grade acrylic,and stainless steel. Such materials which are in extended contact withthe contents of the reservoir subassembly preferably pass ISO 10-993 andother applicable biocompatibility testing.

The reservoir of the reservoir subassembly is further preferably able tobe stored for the prescribed shelf life of the reservoir contents inapplicable controlled environments without adverse effect to thecontents and is capable of applications in a variety of environmentalconditions. Additionally, the barrier provided by the components of thereservoir do not permit the transport of gas, liquid and solid materialsinto or out of the contents at a rate greater than that allowable tomeet the desired shelf life. In the embodiments shown above, thereservoir subassembly materials are capable of being stored and operatedin a temperature range of approximately 0 to 120 degrees F., and canhave a shelf life of two or more years. Other variations of materialsmay be selected which allow for thermal cycles to room temperature andback to cold storage, as well as other temperature operating ranges,beyond 0 to 120 degrees F.

In addition to satisfying stability requirements, the reservoir canfurther ensure operation by successfully passing any number of leaktests, such as holding a 30 psi sample for 20 minutes without leaking.Additional filling, storage and delivery benefits resulting from theconfiguration of the reservoir subassembly include minimized headspaceand adaptability as described in greater detail below.

The reservoir of the reservoir subassembly is preferably evacuated priorto filling, as described in greater detail below. By evacuating thereservoir prior to filling, and having only a slight depression in thehard floor of the rigid portion, headspace and excess waste within thereservoir can be minimized. In addition, the shape of the reservoir maybe configured to adapt to the type of energizing mechanism used, e.g., adisk or Disk spring having any number of diameter and height dimensions.Additionally, using an evacuated flexible reservoir during fillingminimizes any air or bubbles within the filled reservoir. The use of aflexible reservoir is also very beneficial when the device is subjectedto external pressure or temperature variations, which can lead toincreased internal reservoir pressures. In such case, the flexiblereservoir expands and contracts with the contents, thereby preventingpossible leaks due to expansion and contraction forces. Alternatefilling methods may also be employed, such as described in U.S. patentapplication Ser. No. 10/679,271, filed on Oct. 7, 2003 the entirecontents of which is incorporated herein by reference in its entirety.

Yet another feature of the reservoir subassembly includes the ability topermit automated particulate inspection at the time of fill, or by auser at the time of use. One or more reservoir barriers, such as therigid portion, can be molded of a transparent, clear plastic material,which allows inspection of the substance contained within the reservoir.The transparent, clear plastic material is preferably a cyclic olefincopolymer that is characterized by high transparency and clarity, lowextractables and biocompatibility with the substance contained in thereservoir. In such applications, the reservoir includes minimalfeatures, which could possibly obstruct inspection (i.e. rotation duringinspection is permitted).

A fluid path between the reservoir and the patient microneedles in theembodiments described above is constructed of materials similar oridentical to those described above for the reservoir subassembly, andthat satisfy numerous biocompatibility and storage tests. For example,as shown in Table 1 below, where a device content includes insulin, theprimary materials of contact in the reservoir subassembly of theembodiments include linear, low-density polyethylene, cyclic olefincopolymer and Teflon, and can also include a transparent, clear plastic.The primary materials of contact in the remaining flow path between thereservoir subassembly and the microneedles of the patient needlemanifold include polyethylene, medical grade acrylic, and/or stainlesssteel.

TABLE 1 Path Component Material Reservoir Polyethylene, cyclic olefincopolymer and/or Teflon Reservoir Film metal-coated film, such aspolyethylene, aluminum, polyester and/or nylon with a chemical tielayer, such as the product such as the product A83, manufactured byBeacon Converters of Saddle Brook N.J. Cartridge Glass or Plastic (sameas reservoir) or combination thereof. Cartridge Stopper ElastomerPatient Needle Polyethylene and/or medical Manifold grade acrylicPatient Needle Stainless steel Access Needle Stainless Steel

Specifically, the patient needles can be constructed of stainless steel,and patient needle manifold can be constructed of polyethylene and/ormedical grade acrylic. Such materials when in extended contact with thecontents of the reservoir subassembly preferably pass ISO 10-993biocompatibility testing.

As shown in each embodiment above, a disk or Disk spring is included inthe device for applying an essentially even, constant force to thereservoir to force the contents from the reservoir, and is hereinaftersometimes referred to as a constant force spring. The constant forcespring is used to store energy that, when released by device energizing,pressurizes the reservoir at the time of use. The spring is held in aflexed state by a retention disk, or handle, that is positioned at thecenter of a plurality of spring fingers. In doing so, the spring isprevented from putting stress on the film of the reservoir subassemblyor any remaining device components during storage. The retaining disk issufficiently rigid to resist spring tension and deformation, and shouldnot fail under normal tensile load.

Each embodiment described above also contains at least one patientneedle, or microneedle, but may contain several, such as the threemicroneedles. Each microneedle is preferably at least 31 gauge orsmaller, such as 34 gauge, and is anchored within a patient needlemanifold which can be placed in fluid communication with the reservoir.The microneedles, when more than one is included in the device, may alsobe of differing lengths, or gauges, or a combination of both differinglengths and gauges, and can contain one or more ports along a bodylength, preferably located near the tip of the needle or near the tipbevel if the needle has one.

In the embodiments described above, the use of multiple 34 gauge needlesto deliver the reservoir contents is practical as the infusion occursover a longer period than typically associated with an immediate syringeinjection requiring a much larger cannula, or needle. In the disclosedembodiments, any microneedles can be used which target either anintradermal or subcutaneous space, however, the embodiments shown aboveinclude intradermal microneedles of between 0.5 and 4 mm in length(i.e., 2 mm), and the arrangement of these patient needles can be in alinear or nonlinear array, and can include any number of needles asrequired by the specific application. Alternatively, other lengths andgages may be used for parenteral delivery to other tissue spaces.

The patient needles are positioned in a patient needle manifold. In thepatient needle manifold of each embodiment described above, at least onefluid communication path, or feed channel, is provided to each patientneedle. The manifold may simply have a single path to one or morepatient needles, or may provide multiple fluid paths or channels routingcontents to each needle separately. These paths or channels may furthercomprise a tortuous path for the contents to travel, thereby affectingfluid pressures and rates of delivery, and acting as a flow restrictor.The channels or paths within the patient needle manifold can range inwidth, depth and configuration depending upon application, where channelwidths are typically between about 0.015 and 0.04 inch, preferably 0.02inch, and are constructed to minimize dead space within the manifold.

The devices and methods described herein are suitable for use inadministering various substances, including medications andpharmaceutical agents, to a patient, and particularly to a humanpatient. As used herein, a pharmaceutical agent includes a substancehaving biological activity that can be delivered through the bodymembranes and surfaces, and particularly the skin. Examples, listed ingreater detail below, include antibiotics, antiviral agents, analgesics,anesthetics, anorexics, antiarthritics, antidepressants, antihistamines,anti-inflammatory agents, antineoplastic agents, vaccines, including DNAvaccines, and the like. Other substances that can be deliveredintradermally or subcutaneously to a patient include human growthhormone, insulin, proteins, peptides and fragments thereof. The proteinsand peptides can be naturally occurring, synthesized or recombinantlyproduced. Additionally, the device can be used in cell therapy, asduring intradermal infusion of dendritic cells. Still other substanceswhich can be delivered in accordance with the method of the presentinvention can be selected from the group consisting of drugs, vaccinesand the like used in the prevention, diagnosis, alleviation, treatment,or cure of disease, with the drugs including Alpha-1 anti-trypsin,Anti-Angiogenesis agents, Antisense, butorphanol, Calcitonin andanalogs, Ceredase, COX-II inhibitors, dermatological agents,dihydroergotamine, Dopamine agonists and antagonists, Enkephalins andother opioid peptides, Epidermal growth factors, Erythropoietin andanalogs, Follicle stimulating hormone, G-CSF, Glucagon, GM-CSF,granisetron, Growth hormone and analogs (including growth hormonereleasing hormone), Growth hormone antagonists, Hirudin and Hirudinanalogs such as hirulog, IgE suppressors, Insulin, insulinotropin andanalogs, Insulin-like growth factors, Interferons, Interleukins,Leutenizing hormone, Leutenizing hormone releasing hormone and analogs,Low molecular weight heparin, M-CSF, metoclopramide, Midazolam,Monoclonal antibodies, Narcotic analgesics, nicotine, Non-steroidanti-inflammatory agents, Oligosaccharides, ondansetron, Parathyroidhormone and analogs, Parathyroid hormone antagonists, Prostaglandinantagonists, Prostaglandins, Recombinant soluble receptors, scopolamine,Serotonin agonists and antagonists, Sildenafil, Terbutaline,Thrombolytics, Tissue plasminogen activators, TNF-, and TNF-antagonist,the vaccines, with or without carriers/adjuvants, includingprophylactics and therapeutic antigens (including but not limited tosubunit protein, peptide and polysaccharide, polysaccharide conjugates,toxoids, genetic based vaccines, live attenuated, reassortant,inactivated, whole cells, viral and bacterial vectors) in connectionwith, addiction, arthritis, cholera, cocaine addiction, diphtheria,tetanus, HIB, Lyme disease, meningococcus, measles, mumps, rubella,varicella, yellow fever, Respiratory syncytial virus, tick bornejapanese encephalitis, pneumococcus, streptococcus, typhoid, influenza,hepatitis, including hepatitis A, B, C and E, otitis media, rabies,polio, HIV, parainfluenza, rotavirus, Epstein Barr Virus, CMV,chlamydia, non-typeable haemophilus, moraxella catarrhalis, humanpapilloma virus, tuberculosis including BCG, gonorrhoea, asthma,atheroschlerosis malaria, E-coli, Alzheimer's, H. Pylori, salmonella,diabetes, cancer, herpes simplex, human papilloma and the like othersubstances including all of the major therapeutics such as agents forthe common cold, Anti-addiction, anti-allergy, anti-emetics,anti-obesity, antiosteoporeteic, anti-infectives, analgesics,anesthetics, anorexics, antiarthritics, antiasthmatic agents,anticonvulsants, anti-depressants, antidiabetic agents, antihistamines,anti-inflammatory agents, antimigraine preparations, antimotion sicknesspreparations, antinauseants, antineoplastics, antiparkinsonism drugs,antipruritics, antipsychotics, antipyretics, anticholinergics,benzodiazepine antagonists, vasodilators, including general, coronary,peripheral and cerebral, bone stimulating agents, central nervous systemstimulants, hormones, hypnotics, immunosuppressives, muscle relaxants,parasympatholytics, parasympathomimetrics, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,sedatives, sexual hypofunction and tranquilizers and major diagnosticssuch as tuberculin and other hypersensitivity agents as described inU.S. Pat. No. 6,569,143, entitled “Method of Intradermally InjectingSubstances”, the entire content of which is expressly incorporatedherein by reference.

Vaccine formulations which can be delivered in accordance with thesystems and methods of aspects of the present invention can be selectedfrom the group consisting of an antigen or antigenic composition capableof eliciting an immune response against a human pathogen, which antigenor antigenic composition is derived from HIV-1, (such as tat, nef, gp120or gp160), human herpes viruses (HSV), such as gD or derivatives thereofor Immediate Early protein such as ICP27 from HSVI or HSV2,cytomegalovirus (CMV (esp. Human) (such as gB or derivatives thereof),Rotavirus (including live-attenuated viruses), Epstein Barr virus (suchas gp350 or derivatives thereof), Varicella Zoster Virus (VZV, such asgp1, II and IE63) or from a hepatitis virus such as hepatitis B virus(for example Hepatitis B Surface antigen or a derivative thereof),hepatitis A virus (HAV), hepatitis C virus and hepatitis E virus, orfrom other viral pathogens, such as paramyxoviruses: RespiratorySyncytial virus (RSV, such as F and G proteins or derivatives thereof),parainfluenza virus, measles virus, mumps virus, human papilloma viruses(HPV for example HPV6, 11, 16, 18), flaviviruses (e.g. Yellow FeverVirus, Dengue Virus, Tick-borne encephalitis virus, JapaneseEncephalitis Virus) or Influenza virus (whole live or inactivated virus,split influenza virus, grown in eggs or MDCK cells, or whole fluvirosomes or purified or recombinant proteins thereof, such as HA, NP,NA, or M proteins, or combinations thereof), or derived from bacterialpathogens such as Neisseria spp, including N. gonorrhea and N.meningitidis (for example capsular polysaccharides and conjugatesthereof, transferrin-binding proteins, lactoferrin binding proteins,PilC, adhesins); S. pyogenes (for example M proteins or fragmentsthereof, C5A protease, lipoteichoic acids), S. agalactiae, S. mutans; H.ducreyi; Moraxella spp, including M catarrhalis, also known asBranhamella catarrhalis (for example high and low molecular weightadhesins and invasins); Bordetella spp, including B. pertussis (forexample pertactin, pertussis toxin or derivatives thereof, filamenteoushemagglutinin, adenylate cyclase, fimbriae), B. parapertussis and B.bronchiseptica; Mycobacterium spp., including M. tuberculosis (forexample ESAT6, Antigen 85A, -B or -C), M. bovis, M. leprae, M. avium, M.paratuberculosis M. smegmatis; Legionella spp, including L. pneumophila;Escherichia spp, including enterotoxic E. coli (for example colonizationfactors, heat-labile toxin or derivatives thereof, heat-stable toxin orderivatives thereof), enterohemorragic E. coli, enteropathogenic E. coli(for example shiga toxin-like toxin or derivatives thereof); Vibrio spp,including V. cholera (for example cholera toxin or derivatives thereof);Shigella spp, including S. sonnei, S. dysenteriae, S. flexnerii;Yersinia spp, including Y. enterocolitica (for example a Yop protein),Y. pestis, Y. pseudotuberculosis; Campylobacter spp, including C. jejuni(for example toxins, adhesins and invasins) and C. coli; Salmonella spp,including S. typhi, S. paratyphi, S. choleraesuis, S. enteritidis;Listeria spp., including L. monocytogenes; Helicobacter spp, includingH. pylori (for example urease, catalase, vacuolating toxin); Pseudomonasspp, including P. aeruginosa; Staphylococcus spp., including S. aureus,S. Epidermidis; Enterococcus spp., including E. faecalis, E. faecium;Clostridium spp., including C. tetani (for example tetanus toxin andderivative thereof), C. botulinum (for example Botulinum toxin andderivative thereof), C. difficile (for example clostridium toxins A or Band derivatives thereof); Bacillus spp., including B. anthracis (forexample botulinum toxin and derivatives thereof); Corynebacterium spp.,including C. diphtheriae (for example diphtheria toxin and derivativesthereof); Borrelia spp., including B. Burgdorferi (for example OspA,OspC, DbpA, DbpB), B. garinii (for example OspA, OspC, DbpA, DbpB), B.afzelii (for example OspA, OspC, DbpA, DbpB), B. andersonii (for exampleOspA, OspC, DbpA, DbpB), B. Hermsii; Ehrlichia spp., including E. equiand the agent of the Human Granulocytic Ehrlichiosis; Rickettsia spp,including R. rickettsii; Chlamydia spp., including C. Trachomatis (forexample MOMP, heparin-binding proteins), C. pneumoniae (for exampleMOMP, heparin-binding proteins), C. psittaci; Leptospira spp., includingL. interrogans; Treponema spp., including T. pallidum (for example therare outer membrane proteins), T. denticola, T. hyodysenteriae; orderived from parasites such as Plasmodium spp., including P. Falciparum;Toxoplasma spp., including T. gondii (for example SAG2, SAG3, Tg34);Entamoeba spp., including E. histolytica; Babesia spp., including B.microti; Trypanosoma spp., including T. cruzi; Giardia spp., includingG. lamblia; Leshmania spp., including L. major; Pneumocystis spp.,including P. Carinii; Trichomonas spp., including T. vaginalis;Schisostoma spp., including S. mansoni, or derived from yeast such asCandida spp., including C. albicans; Cryptococcus spp., including C.neoformans, as described in PCT Patent Publication No. WO 02/083214,entitled “Vaccine Delivery System”, the entire content of which isexpressly incorporated herein by reference.

These also include other preferred specific antigens for M.tuberculosis, for example Tb Ra12, Tb H9, Tb Ra35, Tb38-1, Erd 14, DPV,MTI, MSL, mTTC2 and hTCC1. Proteins for M. tuberculosis also includefusion proteins and variants thereof where at least two, preferablythree polypeptides of M. tuberculosis are fused into a larger protein.Preferred fusions include Ra12-TbH9-Ra35, Erd14-DPV-MTI, DPV-MTI-MSL,Erd14-DPV-MTI-MSL-mTCC2, Erd14-DPV-MTI-MSL, DPV-MTI-MSL-mTCC2,TbH9-DPV-MTI. Most preferred antigens for Chlamydia include for examplethe High Molecular Weight Protein (HWMP), ORF3, and putative membraneproteins (Pmps). Preferred bacterial vaccines comprise antigens derivedfrom Streptococcus spp, including S. pneumoniae (for example capsularpolysaccharides and conjugates thereof, PsaA, PspA, streptolysin,choline-binding proteins) and the protein antigen Pneumolysin (BiochemBiophys Acta, 1989, 67, 1007; Rubins et al., Microbial Pathogenesis, 25,337-342), and mutant detoxified derivatives thereof. Other preferredbacterial vaccines comprise antigens derived from Haemophilus spp.,including H. influenzae type B (“Hib”, for example PRP and conjugatesthereof), non typeable H. influenzae, for example OMP26, high molecularweight adhesins, P5, P6, protein D and lipoprotein D, and fimbrin andfimbrin derived peptides or multiple copy variants or fusion proteinsthereof. Derivatives of Hepatitis B Surface antigen are well known inthe art and include, inter alia, PreS1, PreS2 S antigens. In onepreferred aspect the vaccine formulation of the invention comprises theHIV-1 antigen, gp120, especially when expressed in CHO cells. In afurther embodiment, the vaccine formulation of the invention comprisesgD2t as hereinabove defined.

The embodiments of the present invention described herein include apush-surface (i.e. push button) design wherein the device can bepositioned and affixed to a skin surface, and energized and/or activatedby gently pressing a push button or push surface. Specifically, the userfirst removes the device from a sterile packaging and may also remove anadhesive cover (not shown) and/or a needle cap. Upon removal of thedevice from the package and prior to use, the features described aboveallows the user to inspect both the device and the contents therein,including inspection for missing or damaged components, expirationdates(s), hazy or color-shifted drugs, and so forth. After use, the usercan once again inspect the device to ensure the entire dose wasdelivered. In this regard, the device can include an administered doseindicator for example, a readable gauge area that is at least 20% of thesurface area of the device housing and accurate to within +/−10% of thelabeled dose. The next step is the reconstitution step. The device caninclude a receiving port for the receipt of a drug container, whichinteracts with the contents of the reservoir within the housing to forma reconstituted medicament solution.

The next step is the positioning and application of the device to theuser's skin surface. Like a patch, the user firmly presses the deviceonto the skin. The device includes a bottom surface having an adhesivelayer to secure the device to the skin of the user. This bottom surfacecan be flat, contoured, or shaped in any suitable fashion, and includesan adhesive layer thereon, which would most likely be covered prior toshipping. Prior to use, the user peels back the adhesive covering, suchas a film covering the adhesive, thereby exposing the adhesive forplacement against the skin, if it has not already been removed inconjunction with the devices de-shielding or sterile package removal.

Once removed, the user is then able to place the device against the skinand press to ensure proper adhesion. As noted above, once properlypositioned, the device may be activated by sliding the button orpressing a push surface. This activation step releases the Disk springallowing it to press against the flexible film of the reservoirsubassembly, pressurizing the reservoir. This activation step also mayalso serve to release the patient needle manifold and seat the patientneedles. Finally, the activation step may also serve to open one or moreof the valve assemblies described above, establishing a fluidcommunication path between the reservoir and the patient needles. Asignificant benefit to each embodiment described above includes theability to achieve each step in a single push button action.Additionally, another significant benefit includes the use of acontinuous fluid communication path comprised of the reservoirsubassembly.

Once activated, the user typically leaves the device in position, orwears the device, for some period of time, such as ten minutes toseventy-two hours for complete delivery of the device contents, and thenremoves and discards the device with no damage to the underlying tissue.However, upon intentional or accidental removal, one or more safetyfeatures can deploy as described in greater detail in US patentapplication of Cindrich et al., Ser. Nos. 10/916,649 and 10/916,648,filed on Aug. 12, 2004.

In addition to the performance advantages described above, anotheradvantage of the embodiments described above is the ability to make twoor more distinct, self-contained subassemblies that allow for assemblyflexibility. Each subassembly is self-contained and stable, and providesthe ability to separate the reservoir assembly or the cartridge assemblyfrom remaining components, allowing separate filling and inspection ofthe reservoir and/or cartridge assembly, while preventing theunnecessary handling of the remaining components. Additionally, shouldany of the additional components be discarded, the costly reservoircontents can be spared and used in another assembly. Also, the reservoircontains no unnecessary parts and as a result, brings a low particleload into filling operations. Also, all stored energy components are inthe body subassembly so they cannot be inadvertently deployed duringfilling of the reservoir. Specifically, no springs are included in thereservoir, which prevents the chance of unwanted spring release duringfilling.

Another aspect of the invention provides methods to reduce bubbleformation upon product reconstitution by using at least a partial vacuumwhile the product is packaged as a dry form. It is theorized that driedproducts which contain some bubble forming components, e.g. surfactant,will upon product reconstitution, generate bubbles, especially whenagitation is needed for reconstitution. For most applications,parenteral solutions must be free of all visible particulate material.Particles measuring 50 microns or larger can be detected by visualinspection. Specialized equipment is needed to detect particles lessthan 50 microns in size. The USP 27/NF 22 Section <788> sets limits onthe number and size of particulates that are permissible in parenteralformulations. For small volume parenterals, the limit is 3000particles/container that are equal to or larger than 10 microns, and notmore than 300/container that are equal to or larger than 25 microns.Therefore, the healthcare professional or the patient need to make surethe solute is completely dissolved and the solution looks clear beforeadministration. The presence of bubbles in the reconstituted solutioncan make the solution appear turbid, which in turn interferes with theobservation and determination of complete dissolution of the product.The turbidity of the solution makes it very difficult to determinewhether bubbles or insoluble particles are present. As previouslymentioned, the latter would not be desirable in an injected product.

Additionally, injection of bubbles can cause serious problems as well.Therefore, healthcare professional and patient have to wait untilbubbles dissipate and the solution looks transparent. It may take quitea long time for bubbles to dissipate especially in a viscous solution.Aspects of methods of present invention dictate that if the driedproduct is packaged and sealed under vacuum or partial vacuum, and ifthe vacuum is not completely released upon reconstitution (e.g. using asyringe to introduce diluent by punching into the stopper of a sealedvial), the vacuum helps to enhance the dissipation of bubbles. Detailscan be found in the following example.

Example I

This example used a freeze dried formulation which contained 216 mg ofan anti-HIV peptide, 200 mg PEG1500 and trace amount of sodium hydroxideand acetic acid in each vial for a desired pH. PEG 1500 helps enhancethe solubility of the anti-HIV peptide. Upon reconstitution of thisformulation, the freeze-dried cake wetted instantly and dissolvedrapidly. Nevertheless dissolution of PEG 1500 generated large amounts ofbubbles and these bubbles took approximately 20 min to dissipate. Toprepare samples for the experiment, the formulation was reconstitutedand reprocessed by freeze-drying and spray freeze-drying using 3 ml or 5ml lyo vials. The vials were sealed under 2000 mT (partial vacuum) oratmospheric pressure. Then a dissolution test was performed and resultscan be found in Table 2. It was observed that a higher partial vacuumremaining in the vial after reconstitution reduces bubble formation. Forinstance, the product dissolution and bubble dissipation with thesamples in the 5 ml vial was more rapid than those in the 3 ml vial andsealed under 2000 mT, despite that the sample amount in both vials werecomparable. The volume effect of vials on bubble dissipation wasunexpected, and it is theorized that the bigger vial provides morecapacity to maintain higher partial vacuum than smaller vials afterdiluent was added. With the same vial size of 3 ml, the vials sealedunder 2000 mT had less bubble formation than those sealed at 1 ATM. Itis theorized that the vacuum helps the bubbles escape from the solutionand therefore, the solution clears faster.

TABLE 2 Result of reconstitution test of freeze-dried and sprayfreeze-dried anti-HIV peptide and PEG 1500 formulations. VisualObservation of Dissolution Recons. Water Properties, in minutes DryPowder For Injection Fully Completely Bubbles Qualitative Powder Weightvolume Wet Dissolve clear Vacuum Bubble Processing (g) (ul) Purity (min)(min) (min) in vial Vial type formation Freeze 186 384 100% <1 ~10 20ATM 3 ml +++ Dried Wheaton 214 443 ND <1 ~10 18 2000 mT 3 ml ++ Wheaton211 436 ND <1 ~10 18 2000 mT 3 ml ++ Wheaton 207 428 ND <1 ~10 18 2000mT 3 ml ++ Wheaton Spray 184 381 100% 3 12 15 ATM 3 ml +++ FreezeWheaton Dried 174 359 ND <1 5 8 2000 mT 5 ml + Kimble 168 347 ND <1 8 112000 mT 5 ml + Kimble 133 276 ND <1 10 20 ATM 3 ml +++ Wheaton

Unlike prior art methods; the methods and devices of bubble reductionaccording to aspects of the present invention can be convenientlyapplied during small and large-scale product manufacturing andpackaging. The vacuum may be applied during the initial bottle/vialsealing, as in the manufacturing of the drug container or cartridge. Inanother embodiment, the vacuum may be also induced by special deviceupon reconstitution.

Example II

It may be desirable to maintain the pressure in the drug container belowatmospheric pressure throughout the process of reconstitution of themedicament. For this purpose, initial evacuation of the container to apressure less than about 50 Torr is expected to be adequate as the vaporpressure introduced by the diluent is minimal. The vapor pressure ofwater at 22 C is 20 Torr. Once mixed the vapor pressure of thereconstituted aqueous medicament would generally be lower.

For example, in a drug reservoir of 1 ml volume, and an initial pressureof 2 Torr, the ideal gas law allows an estimate of the expected finalpressure:

P ₁ V ₁ =P ₂ V ₂

Filling the container with 0.99 ml diluent, the final pressure due tothe initial gas in the reservoir (P₂) is:

2 T×1 ml=P ₂×(1−0.99) ml

The total pressure can be estimated as the sum of the partial pressuresfrom the initial gas in the reservoir and the diluent.

P ^(total) =P ^(vap) +P ₂=20 T+2×1/0.01=220 T

As a second example, with 50 Ton initial pressure, adding 0.9 mldiluent:

P ₂=20+50×1/0.1=520 T

In both examples, the final pressure remains sub atmospheric.

Although only a few exemplary embodiments of the present invention havebeen described in detail above, those skilled in the art will readilyappreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention. We claim:

1. A method for reducing the formation of bubbles in a reconstitutedformulation comprising: providing a pre-determined amount of medicamentformulation within a container at a pre-determined first pressure,wherein said pre-determined pressure is less than atmospheric pressure;adding a pre-determined volume of liquid diluent to said containerwherein when said diluent is added to said container said container hasa pre-determined second pressure; mixing said medicament formulation andsaid liquid diluent at said second pressure within said container toform said reconstituted formulation; and mixing said reconstitutedformulation in an atmosphere substantially comprised of an inert gas. 2.A method according to claim 1 wherein said second pressure is less thanatmospheric pressure.
 3. A method according to claim 1 wherein saidfirst pressure is greater than 2000 mT of vacuum.
 4. A method accordingto claim 2 wherein said second pressure is between 2000 mT of vacuum,and atmospheric pressure.
 5. A method according to claim 1 wherein saidmedicament is a lyophilized powder.
 6. A method according to claim 1wherein said medicament is a spray freeze-dried powder.
 7. A methodaccording to claim 2 wherein said medicament is a lyophilized powder. 8.A method according to claim 2 wherein said medicament is a sprayfreeze-dried powder.
 9. A method according to claim 3 wherein saidmedicament is a lyophilized powder.
 10. A method according to claim 3wherein said medicament is a spray freeze-dried powder.
 11. A methodaccording to claim 1 wherein said medicament is a liposome.
 12. A methodaccording to claim 1 wherein said medicament is a substantially drypowder.
 13. A method according to claim 2 wherein said medicament is aliposome.
 14. A method according to claim 2 wherein said medicament is asubstantially dry powder.
 15. A method according to claim 3 wherein saidmedicament is a liposome.
 16. A method according to claim 3 wherein saidmedicament is a substantially dry powder.
 17. A method according toclaim 1 wherein said inert gas is selected from the group consisting ofargon and helium.
 18. A method for reducing the formation of bubbles ina reconstituted formulation comprising: providing a pre-determinedamount of medicament formulation within a container at a pre-determinedfirst pressure, wherein said pre-determined first pressure is less thanatmospheric pressure; adding a pre-determined volume of liquid diluentat a predetermined second pressure to said container wherein when saiddiluent is added to said container said container has a pre-determinedthird pressure, wherein said second pressure is less than atmosphericpressure; and mixing said medicament formulation and said liquid diluentat said third pressure within said container to form said reconstitutedformulation.